Project 2 Summary - Abstract In acquired sensorineural hearing loss, the dogma has been that hair cells, as primary targets, are the first to degenerate, and that cochlear nerve fibers die only after the hair cells disappear. Recent animal work in the Kujawa and Liberman laboratories has shown, in both noise-induced and age-related hearing loss, that the most vulnerable elements are actually the synaptic connections between hair cells and cochlear neurons, and that this cochlear synaptopathy can be widespread (> 50%) even in ears with no threshold elevation and no hair cell degeneration. Synaptic loss silences the affected neurons, absent a cochlear implant, however the slow death of the cell bodies and central projections offers a long therapeutic window in which neurotrophin-related therapies could potentially reverse the damage. We hypothesize that partial de-afferentation of surviving inner hair cells is widespread in acquired sensorineural hearing loss and is a major cause of difficulties understanding speech in a noisy environment, regardless of the degree of hair cell damage, as measured by the audiogram. A recent pilot study from the Liberman lab showed that the same immunostaining techniques we developed to quantify cochlear synaptopathy in mouse, rat, guinea pig, rhesus and other mammals can be applied to human post-mortem material. An analysis of a small number of ears without explicit otologic disease revealed significant cochlear synaptopathy in aged ears, despite no significant loss of hair cells. Here we propose to build on these preliminary results to quantify, as broadly as possible, the prevalence of cochlear de- afferentation in a wide range of hearing loss etiologies, using newly acquired human temporal bones as well as archival sections from the Mass. Eye and Ear collection. Specifically we will, quantify cochlear afferent and efferent innervation in age-graded ?normal-hearing? subjects (Aim 1) and characterize cochlear synaptopathy in subjects with sensorineural hearing loss (Aim 2), with etiologies including noise damage, aminoglycoside antibiotics, and cisplatin-based chemotherapy. Completion of these foundational studies will reveal how widespread the problem of primary neural degeneration is across the spectrum of sensorineural hearing loss in human ears.